Abstract Crohn?s disease (CD) is a chronic, heterogeneous inflammatory disease that causes damage to the gastrointestinal tract. There is no cure for CD. Research that furthers our understanding of CD may give rise to more effective diagnostic markers and therapeutics. Macrophages are an integral part of the immune system. Their job is to engulf harmful microbes, digest them and prime T cells and B cells for an adaptive response. There are marked differences in lamina propria macrophage (LP M?) function in health when compared with CD. LP M?s from CD patients have the ability to secrete inflammatory cytokines and promote Th1 and Th17 immune responses, while LP M?s in health promote more protective T cell responses. The molecular mechanism giving rise to abnormal LP M?s in CD patients remains poorly understood. I hypothesize that altered chromatin accessibility drives the LP M? phenotypic changes that are associated with colitis phenotypes/CD. This hypothesis will be tested through two aims. Aim 1 will determine if manipulation of LP M? accessible chromatin in Il10-/- macrophages is sufficient to restore the physiological LP M? phenotype. Using a high- throughput small molecule screen I determined that inhibitors of bromodomain and extra-terminal domain proteins, such as (+)-JQ1, are sufficient to alter accessible chromatin and prevent inflammation in Il10-/- macrophages. I will evaluate the ability of (+)-JQ1 to decrease genome-wide chromatin accessibility at IL-10 variable accessible regions and to prevent inflammatory cytokine secretion in vitro. I will also determine if treatment of germ free Il10-/- mice with (+)-JQ1 is sufficient to prevent onset of colitis after colonization with specific-pathogen free bacteria. In Aim 2 I will identify and functionally characterize the LP M? regulatory program associated with human CD. For the first part of Aim 2, I will isolate LP M?s from healthy and CD patients and determine genome-wide changes in chromatin accessibility by ATAC-seq and gene expression by RNA-seq in matched unstimulated and bacterially-stimulated samples. For the second part of Aim 2, I will quantify the strength of select accessible chromatin regions based on their macrophage-specificity, known involvement in inflammatory signaling pathways and if they are known to contain CD associated variants. I will evaluate the ability of these selected regions to bind transcription factors using electrophoretic mobility shift assays and will evaluate their impact on levels of transcription by luciferase reporter assays. Together, these aims will highlight that changes in LP M? chromatin accessibility contributes significantly to altered LP M? function in the pathogenesis of CD and fulfil my technical requirements as a Ph.D. candidate in the curriculum in Genetics and Molecular Biology.